Solid phase chemical synthesis of DNA fragments is routinely performed using protected nucleoside phosphoramidites. Beaucage et al. (1981) Tetrahedron Lett. 22:1859. In this approach, the 3′-hydroxyl group of an initial 5′-protected nucleoside is first covalently attached to the polymer support. Pless et al. (1975) Nucleic Acids Res. 2:773. Synthesis of the oligonucleotide then proceeds by deprotection of the 5′-hydroxyl group of the attached nucleoside, followed by coupling of an incoming nucleoside-3′-phosphoramidite to the deprotected hydroxyl group. Matteucci et al. (1981) J. Am. Chem. Soc. 103:3185. The resulting phosphite triester is finally oxidized to a phosphotriester to complete one round of the synthesis cycle. Letsinger et al. (1976) J. Am. Chem. Soc. 98:3655. The steps of deprotection, coupling and oxidation are repeated until an oligonucleotide of the desired length and sequence is obtained. Optionally, after the coupling step, the product may be treated with a capping agent designed to esterify failure sequences and cleave phosphite reaction products on the heterocyclic bases.
Solid phase polynucleotide synthesis results in a polynucleotide bound upon a solid support. Typically, an additional step releases the polynucleotide from the solid support after the polynucleotide strand has been synthesized. This release step yields the polynucleotide in solution, which may then be separated from the solid support, e.g. by filtration or other suitable methods. The release step is dependent upon having a support that is functionalized with a releasable moiety that, while inert under the conditions used in the synthesis cycle, provides for the release of the synthesized polynucleotide under conditions conducive for doing so.
The concept of a “safety catch linker” has been exploited widely. These linkers were originally developed by Kenner for peptide synthesis (Kenner et al. (1971) J. Chem. Soc. Chem. Commun. pp 636-37). They were designed to be cleaved in a two-stage process, where the first step involves activation of a functional group on the linker, and the second step involves the actual cleavage of the linker. After the functional group has been activated the cleavage step is more facile than it would have been prior to activation. Kenner's safety catch linker is stable to both acidic and basic conditions until the nitrogen is alkylated (activation), then cleaved by nucleophilic attack, for example with hydroxide or nucleophilic amine.

Another example of a safety catch linker, developed by Marshall and Liener (Marshall, D. L.; Liener, I. E., J. Org. Chem., 1970, 35, 867-868), exploits the activation of a sulfide by oxidation to the sulfone. After activation with hydrogen peroxide, the linker is cleaved with an amine nucleophile.

The concept of “safety catch linkers” has been further explored with a variety of type of activation methods prior to cleavage of the linker: most activation steps are performed through alkylation, oxidation, or neighboring group effects. However, these previously described processes are performed as two independent steps often requiring several independent reagents.
While there are examples of cleavable linkers in the literature, there remains a need for novel cleavable linkers for polynucleotides, e.g. polynucleotides bound to a substrate.